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Objective: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin.Methods: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21.Results: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity.Conclusions: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy. [ABSTRACT FROM AUTHOR]

The article presents phenotypic and genetic findings of 42 individuals from 21 families with mutations of valosin-containing protein (VCP) genes. Eighteen patients manifested a previously described mutation. The study measured serum creatine kinase (CK) levels in 19 patients. Some patients showed mild, unspecific myopathic changes.

Introduction: Marfan's syndrome (MFS) is the commonest inherited disorder of connective tissue. It is defined by major features in the cardiovascular, skeletal and ocular systems, and minor features in the integument and lungs. Patients who fulfil the diagnostic criteria have a mutation in the fibrillin (FBN1) gene, which encodes a major glycoprotein in the microfibrillar system, including in perimysium and endomysium. Muscle involvement, although in the original description, has not been mentioned at all recently. Materials and methods: We studied a family with MFS in whom myopathy led to respiratory failure. Genetic analyses on venous blood and immunohistochemical studies of muscle biopsies were carried out. Results: Single stranded conformational polymorphism screening of all exons of the FBN1 gene revealed a C4621 T base change in exon 37. This was predicted to result in the production of a truncated form of FBN1. Immunohistochemical studies showed conspicuous abnormalities in endomysial and perimysial fibrillin. Conclusion: This is the first demonstration of fibrillin deficiency in muscle in MFS and its implications for biomechanical function are discussed. [ABSTRACT FROM AUTHOR]

MYO18B is an unconventional class XVIII myosin predominantly expressed in skeletal muscle and heart. Recessive pathogenic MYO18B variants are a rare cause for Klippel-Feil syndrome (KFS) with facial dysmorphism, short stature, myopathy and less frequently cardiomyopathy. MYO18B variants were tentatively associated with nemaline myopathy; however, the reported muscle manifestations are variable and poorly characterized. Here we provide clinical and genetic characterization of four patients from three families with a myopathy due to biallelic truncating MYO18B variants manifesting with childhood onset weakness, without KFS or cardiomyopathy. Muscle involvement in our series was characterized by facial, axial with severe neck flexion weakness, and proximal involvement. Congenital findings were noted in three patients including hip dislocation, reduced fetal movements and arthrogryposis with diffuse hypotonia. Marked intrafamilial variability of muscle involvement was noted in the two siblings as recognition of symptoms in one sibling was not until early childhood. Both siblings had similar facial dysmorphisms and short stature. The clinical findings of myopathy were supported by myopathic muscle histology in two patients, including variation in fiber size, type I fiber predominance, and cores in one with an absence of rods. Lower extremity muscle MRI in two patients showed striking involvement of the rectus femoris and semitendinosus. Our series confirms presence of mild dysmorphic features, noted in all patients, and short stature, present in two. The constellation of facial dysmorphism and myopathy is emerging as a characteristic feature of MYO18B-related disorders, while the presence of nemaline rods on muscle biopsy, cardiomyopathy and KFS are more variable. Additional patients and formal natural history studies are needed to gain further insight in the clinical spectrum and potential genotype-phenotype correlations associated with biallelic MYO18B variants. [ABSTRACT FROM AUTHOR]

Distal arthrogryposis (DA) is a clinically and genetically heterogeneous condition with mutations in at least five genes encoding for sarcomeric proteins (TNN12, TNNT3, TPM2, MYH3 and MYH8) implicated to date. A significant proportion of cases remain genetically uncharacterised. Here we describe 4 members from a 3 generation consanguineous Irish family that presented with a congenital myopathy resembling King-Denborough syndrome (KDS), characterized by clinical features of ptosis and distal arthrogryposis, and cores on muscle biopsy. Through collaboration with The Sanger Centre as part of the UK10K project, we exome screened these subjects and were able to identify a segregating homozygous misssense mutation in exon 2 of the Endothelin converting enzyme like 1 (ECEL1) gene, recently found to be responsible for DA5D. Population screening enabled us to find two additional DA families that harboured causative variants ECEL1 exons 2 and 15, respectively, reinforcing the notion of a causative link between ecel1 dysfunction and the DA’s. ECEL1 encodes for a type2 transmembrane M13 metallopeptidase with an as yet unidentified substrate, localised to the endoplasmic reticulum and plasma membrane of the central nervous system (CNS). The ecel1 protein is also expressed in skeletal muscle and thought to participate in the formation of the neuromuscular junction (NMJ), but its precise function is currently unknown. We therefore embarked on protein function assays in zebrafish morphants and ECEL1-mutated patient fibroblasts. In particular, we knocked down (KD) ecel1 in zebra fish embryo applying a morpholino approach and found a gross defect in body axis curvature leading to perturbed functional abilities. Microscopic examination revealed disorganised/detached myofibres that have intact sarcolemma. (We have also obtained a zebrafish ecel1 knock out (KO) model achieved by insertion of a null allele by chemical mutagenesis. This model does not exhibit the same trunk curvatur. [ABSTRACT FROM AUTHOR]

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy (NM), cap myopathy, core-rod myopathy, congenital fibre-type disproportion, core-rod myopathy, distal arthrogryposes and Escobar syndrome. Here we correlate the clinical picture of these diseases with novel (16) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. A total of 27 Twenty-seven distinct pathogenic variants of TPM2, and 20 of TPM3, have been published or listed in the Leiden Open Variant Database ( http://www.dmd.nl/ ). Most are heterozygous changes associated with autosomal dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2 + sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotypes more often had contractures of the limb joints (18/19) and jaw (6/19) than those with non-hypercontractile ones (2/22 and 1/22), while patients with the non-hypercontractile molecular phenotypes more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding. [ABSTRACT FROM AUTHOR]

Abstract: Desminopathies are intermediate filament disorders with a mainly dominant autosomal inheritance pattern, characterized by skeletal myopathy and/or cardiomyopathy with average onset in the 3rd decade. The clinical phenotype caused by desmin mutations is described as a myofibrillar myopathy (MFM). This term refers to a group of genetically heterogeneous neuromuscular disorders that share histopathological features of cytoplasmic aggregates of multiple proteins, including desmin, αB-crystallin and myotilin on muscle biopsy. We report on two siblings from healthy, non-consanguineous parents presenting with progressive generalized proximal more than distal muscle weakness in legs and arms from the age of 3years, facial weakness and ptosis, reduced upward gaze, scapular winging, ankle contractures, mild calf hypertrophy, and swallowing difficulties. No cardiac involvement was detected so far. Creatine kinase levels were raised up to 800 and 1000IU/L. A muscle MRI of the thigh showed more severe involvement of the posterior compartment with relative sparing of the sartorius and gracilis muscles. Muscle histopathology showed myopathic features with atrophic fibers, nuclear bags, internal nuclei and type 1 fibre predominance with remarkably complete absence of desmin labelling which was confirmed by Western blot. Mutation analysis revealed two compound heterozygous mutations in exon 1 of desmin gene resulting in premature stop codons. This novel clinical phenotype linked to autosomal recessive desminopathy widens the clinical spectrum of this class of disease. [Copyright &y& Elsevier]